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1Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Ontario M5S 1A8; 2Department of Surgery, Division of Neurosurgery, The Toronto Western Hospital, Toronto, Ontario M5T 2S8; and 3Toronto Western Research Institute, Applied and Interventional Research, Toronto, Ontario M5T 2S8, Canada
Submitted 26 August 2003; accepted in final form 10 October 2003
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ABSTRACT |
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INTRODUCTION |
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) appear to code the highly specialized aspects of planning and execution of sequential tasks. For example, monkey cortical neurons have been found to respond to the serial order of the elements (1st, 2nd, 3rd) independent of the nature of a manual task (push, pull, turn) or direction of eye movement (Lu et al. 2002). Recordings of pallidal neurons in monkeys performing a remembered task and a tracking sequential task (Mushiake and Strick 1995) revealed neurons responding preferentially during the memory task and just one of the three reaches, consistent with a role of the basal ganglia in the internal control and ordering of movements. Imaging studies in humans also indicate basal ganglia activation during the execution of sequential movements (Jueptner et al. 1997). Anatomical tracttracing studies support the existence of recurrent neural pathways from the motor cortex to the thalamus via the basal ganglia (Alexander et al. 1990) termed "corticopallidothalamic loops," which are implicated in motor as well as nonmotor functions. However, few studies have examined the possible distributed nature of such responses in these recurrent pathways at subcortical levels and none specifically in motor thalamus. Studies of thalamic neurons during stereotactic procedures typically are limited to determination of responses to passive and active arm movements and classification as "kinesthetic" or "voluntary" (Lenz et al. 1988). We wished to test responses during more complex tasks to determine if these known cell types had higher-level functions. We have now identified neurons in the human motor thalamus that respond during a sequential button press task with preparatory, delayperiod, task, and phase-specific activity, supporting a role for the motor thalamus in internally and externally generated movements. |
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METHODS |
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; Lozano et al. 1996) were made in the thalamus of 16 patients. Nine patients had Parkinson's disease (PD) and underwent microelectrode-guided implantation of DBS electrodes in the STN in the OFF state (no drugs for 12 h). Seven patients in the non-PD group had microelectrode-guided surgery targeting the thalamus for chronic pain (5), myoclonus (1), and essential tremor (1). The University Health Network Research Ethics Board approved these procedures, and patients gave free and informed consent. During the surgery, we recorded neuronal activity (n = 52) as patients pressed a variable sequence of three of five buttons (P1-P3) in two types of visually guided tasks: an internally generated task with a memorized sequence (MEM) and an externally generated task where each cue was followed with a button press (FOL; see Fig. 1, A and B). During the MEM task, after the Ready LED illuminates, a threenumber sequence was presented by illuminating three of the buttons in sequence, and the patient had to remember this sequence until the ready LED was extinguished (after 6 s) signaling go. The patient then reached to press the memorized sequence on the button pads. The patients returned their hand to their chest between reaches. During the FOL task, no information was given to the patient between the ready-go period. The buttons to be pressed were indicated by illuminating one of the five buttons after the go cue and after each successive button press. The MEM and FOL tasks consisted of eight different sequences. These eight sequences were: 213, 231, 235, 245, 453, 435, 431, and 421 to balance for direction-selective movements. Blocks of MEM and FOL trials were presented randomly. Contralateral electromyographic (EMG) activity of wrist extensors and flexors was recorded along with signals from an accelerometer attached to the back of the patient's hand. The signals were recorded on analog videotape using a VR-100B digital recorder (Instrutech, Port Washington, NY) and analyzed off-line. To rule out the possibility that differences in neuronal responses between MEM and FOL tasks were due to different movements, we measured the reaction time (go to P1) and the movement time (P1-P3) for the tasks. No significant differences in reaction or movement times were found between MEM and FOL tasks (t-test, P < 0.05; see Fig. 1, C and D), and no significant difference was found between the PD patients and the other patients (P < 0.05), likely because the task was slow-paced. Neuronal activity was examined in all trials for each cell and separated into nine epochs based on the following movement cues and parameters: onset of ready to go cue when ready LED extinguished; go cue to movement onset; movement onset to end of first button press (P1); end of P1 to subsequent chest contact; chest contact after P1 to end of second button press (P2); end of P2 to subsequent chest contact; post-P2 chest contact to end of third button press (P3); end of P3 to chest contact; and post-P3 chest contact to start of next trial with ready LED. In cases where delay period activity was observed, an extra epoch "AA" was defined from end of instruction LED to ready cue off. Two-way ANOVA was performed to examine the main effects of task and epoch and the interaction term task*epoch (SAS Software, Cary, NC) using a P value of 0.05. In one neuron where raster plots suggested that responses during movements were changing with repetition of trials, further two-way ANOVAs were carried out on each task separately with epoch and trial as main effects. Post hoc t-test for multiple comparisons were carried out with the Waller-Duncan K-ratio t-test, which compares type I and type II error rates based on Bayesian principles. These multiple range t-test calculated the average neuronal activity in each epoch, ranked them in descending order, and indicated groupings of epochs with and without statistical differences. A neuron was considered to be task selective if it showed one or more epochs that were significantly different between tasks. Cells showing modulations during the delay period (between ready and go) were subjected to further statistical analysis by dividing the delay period epoch into two smaller epochs defined by the end of instruction.
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) and showing the locations of all of the neurons tested were constructed for each patient group (PD and non-PD). Neurons were mapped onto the composite after correction of the stereotactic or anatomical map based on the identification of key physiological landmarks. For the patients undergoing thalamic surgery (non-PD), the location of each neuron was corrected with respect to the anterodorsal border of ventral caudal (Vc) as well as length of the track where cells responded to touch with a delimited receptive field and sites where microstimulation-evoked paraesthesias. For patients undergoing STN surgery for PD, the dorsal and ventral borders of STN and the dorsal border of the substantia nigra pars reticulata (SNr) were used as landmarks to provide any necessary corrections to the location of each neuron, as reported previously (Hutchison et al. 1998). The mediolateral plane was not corrected based on physiological data, and was based on the initial target 10.5 or 12 mm lateral for STN and 14.5 mm lateral for thalamus from the midline coordinates of AC and PC from MR images. |
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RESULTS |
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Phase-specific activity describes a response restricted to a specific aspect or element of the movement sequence. Figure 2B shows an example of a neuron responding preferentially during the third button press of the MEM trial in a thalamic pain patient. There was a strong P3 increase in neuronal activity during MEM trials (ANOVA, df = 1, 8, F = 10.3, P < 0.0001) that was absent during FOL trials. This neuron and the other MEM-selective cells were all localized to the nucleus ventralis oralis anterior (Voa) area of the non-PD group. Another example of phase-specific activity is seen in FOL task in Fig. 2C. At the end of each button press, there was a progressive decrease in activity relative to the background activity (see raster data Fig. 2C); however, the decrease in activity at the end of P3 (end of trial) was significantly greater. This was immediately followed by a robust increase in activity (ANOVA, df = 1, 8, F = 14.25, P < 0.0001) after the completion of the sequence, which was larger than the responses to each of the button presses. This neuron was localized to the nucleus ventralis oralis posterior (Vop) area, and the other FOL selective neurons were distributed throughout the Voa, Vop, and ventrointermedius (Vim).
Delay-period activity found in the epoch between ready and go was present during the MEM task for two of the cells, one of which is shown in Fig. 2C. This neuron responded during the MEM task with a burst of increased activity in the delay period, which was absent during the FOL task. The burst occurred just after the onset of the third light (L3) 2.5 s before go. The neuronal activity after the increased activity burst until the go signal was significantly higher than the activity during the initial 3 s of the delay period (t-test, df = 50, t = -7.95, P < 0.05). This neuron was localized to the Vop area of thalamus of a chronic pain patient. Unlike the cited studies in monkeys, we did not observe selective responses to a particular sequence that would suggest a more direct role in sequential control; however, we did find phase specific activity and likely with more testing of neurons and perhaps more training of the patients, a higher yield of these types of responses would be observed.
The distribution of responsive cells was relatively uniform between the patient groups with 20/33 (61%) cells responding to the task in the non-PD group and 11/19 (58%) cells responding in PD patients. Both PD and non-PD groups had similar numbers of cells showing responses with increases in activity (7 and 8) and decreases in activity (4 and 3); however, PD patients lacked neurons with biphasic (increases and decreases in activity, 0 and 9) responses.
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DISCUSSION |
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Neurophysiological recordings in the monkey basal ganglia have shown selective responses of neurons for sequential movements under internal control rather than visual external control (Hikosaka and Wurtz 1983; Mushiake and Strick 1995). In contrast, the cerebellum has been shown to be involved in movements under external control (Jueptner et al. 1996; Mushiake and Strick 1993). Our study examined the response to sequential button press in the human motor thalamus, which receives inputs from both the pallidum and the cerebellum. MEM-selective neurons were found in the Voa, which is consistent with the anatomical evidence that pallidal output projects to the thalamic Voa area (Percheron et al. 1996), which in turn projects to the SMA, M1, and other premotor areas. The FOL selective neurons were found in many regions of the motor thalamus, i.e., the Vim, Vop, and Voa. While those found in Vim are consistent with anatomical evidence that the cerebellum projects to this thalamic region, the others suggest a wider distribution of such responses. Vim projects to the premotor cortex completing the purported neuronal loop involved in externally generated movements. Some evidence exists for functional specificity of neurons in pallido- and cerebellar-receiving areas of motor thalamus (van Donkelaar et al. 1999), suggesting specific subcircuits may also exist in humans and give rise to task-specific activity observed in this study for internally and externally generated movements.
The phasic burst of activity seen in the delay period of the MEM task is similar to that previously described in cortical neurons during a delayed matching-to-sample task (Fuster 1995). There is an increase in activation during memorization of the sequence to be subsequently performed. It is not likely that this response was related to visual cue information because there were no peaks of neuronal activity at the onset of the first two lights (ready, go). Another possibility is the consolidation of internal information on the third element, which may act as an "end" signal, reporting a completion of the sequence (Tanji 2001). We noted that the PD group lacked neurons with MEM-selective responses as well as neurons with biphasic responses that may reflect striatal dopamine loss leading to dysfunction of a surround inhibitory system hypothesized as a mechanism of basal ganglia function (Mink 1996).
Our observations provide support for the involvement of the thalamus in both internally and externally generated sequential movements. More than half of the neurons tested were task related and responded during the MEM and FOL tasks, and in some cases, the response patterns were task specific. Recordings in monkeys during an analogous button-press task have found GPi and SMA neurons with similar activity to the thalamic neurons observed in this study (Mushiake and Strick 1995; Tanji 2001). Taken together with our results, this suggests that the basal ganglia-thalamo-cortical loop (and possibly also the cerbello-thalamic-cortical pathway) is involved in processing and organizing internally generated sequential movements. The thalamus also receives a large projection from cortex (Ilinsky et al. 1993), and thus we cannot rule out that corticothalamic input contributed directly to the responses observed.
In conclusion, this study has examined motor thalamic neurons on a task combining visual sensory, mnemonic, and motor aspects and demonstrated complex responses including preparatory, delay-period, and phase- and task-specific activity. These findings implicate the motor thalamus in both the planning and organization of sequential manual tasks in humans, a role heretofore ascribed to motor cortex, and suggest that these responses are represented as a distributed network throughout the corticopallidothalamic loop.
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ACKNOWLEDGMENTS |
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M. L. MacMillan was supported by NSERC. A. M. Lozano is a Clinician Scientist with CIHR. This work was supported by the Parkinson Society Canada (W. D. Hutchison).
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FOOTNOTES |
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Address for reprint requests and other correspondence: W. D. Hutchison, Div. Neurosurgery, The Toronto Western Hospital, 399 Bathurst St. WW4-443, Toronto, Ontario M5T 2S8, Canada (E-mail: whutch{at}uhnres.utoronto.ca).
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REFERENCES |
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ABSTRACT
INTRODUCTION
) and PD group (
).
